reviously, in studies involving a semi-homologous system of gnotobiotic newborn pigs and a virulent porcine rotavirus strain (SB-1A) and an avirulent human rotavirus strain (DS-1) and their reassortants, we demonstrated that: (i) the third (VP3), fourth (VP4), ninth (VP7), or tenth (NSP4) porcine rotavirus gene each play an important independent role in the virulence of rotavirus infection in piglets; and (ii) all four of the porcine rotavirus virulence-associated genes are required for the induction of diarrhea and the shedding of rotavirus by piglets. These observations suggested a potential new strategy for attenuation of wild-type human rotaviruses of major epidemiological importance and its application to the development of a safe and effective vaccine. We characterized the VP4 neutralization specificity of the porcine rotavirus Gottfried strain (P1B[6],G4) and showed that it was related in a one-way fashion to human rotavirus P[6] VP4s (see AI000339-21 LID). This finding gave us a rationale to develop a Gottfried-based reassortant vaccine, which incorporates the human rotavirus VP7 (G1, G2 or G3) or VP4 (P1A[8] or P1B[4]) gene of epidemiologic importance. This vaccine can provide (i) the attenuation phenotype of a porcine rotavirus in humans and (ii) antigenic coverage not only for epidemiologically important VP7 and VP4 serotypes but also for P2A[6] serotype which in some parts of the world appears to be of clinical significance. Thus far, we have developed Gott x G1, Gott x G2 and Gott x G3 reassortant vaccines. Additional candidate vaccines are being constructed. We have previously shown for the first time that during a phase III clinical trial of the RRV-based quadrivalent vaccine (RotaShield) conducted in Caracas, Venezuela, between 1992 and 1995, horizontal transmission of the vaccine strains was detected in 15% of the vaccinees and 13% of the placebo recipients.